Targeting PRMT7 elicits anti-AML immunity by promoting MHC-I expression

Protein arginine methylation regulates several cellular functions, including RNA splicing, translation and DNA damage repair. Protein arginine N-methyltransferase (PRMT) dysregulation is often seen in malignant hematopoiesis. PRMT7, the only type III PRMT, catalyzes monomethyl arginine (MMA) modification, but its role in leukemogenesis is elusive. Re-analysis of a previous genome-wide CRISPR/Cas9 screen revealed PRMT7 to be a crucial negative-regulator of MHC-I, prompting us to ask whether PRMT7 inhibition might promote anti-AML immunity. To assess the potential PRMT7 function in MHC-I presenting, we knocked out PRMT7 in human AML lines including THP-1 and Molm13 and assessed MHC-I levels. Relative to controls, PRMT7 KO remarkably upregulated MHC-I expression in both lines. We also observed MHC-I upregulation was also observed in both cell lines after treatment with the targeted degrader (PRMT7 PROTAC) ex-vivo at relatively low concentrations, while the same dose of either compound spared normal hematopoietic stem/progenitor (CD34 + ) cells. To confirm MHC-I dynamics in an MLL-AF9 mouse model, we generated a Prmt7 KO MLL-MA9 mouse model from hematopoietic-specific Prmt7 KO mice (Prmt7 fl/fl ;Vav1-Cre) and observed 2-fold upregulation of H-2Kb expression relative to WT MLL-AF9 cells.Given the critical role of MHC-I in CD8 + T cell activation, we next asked whether PRMT7 deletion would enhance CD8 + T cell responses. We evaluated human T cell killing effects in PRMT7-KO/-WT THP-1 or Molm13 cells cocultured with activated CD8 + T cells derived from healthy donors. Post-coculture, we found that PRMT7 KO AML cells were more susceptible to human T cell-mediated killing. In agreement, PRMT7 KO murine AML cells were more sensitive to mouse T cell-mediated killing using a coculture model of MA9 and syngeneic active CD8 + T cells. Moreover, following PRMT7 PROTAC pretreatment, THP1 cells were more sensitive to human T cells mediated killing in a coculture system of THP1 cells and CD8 + T cells.Next, to assess whether PRMT7 deletion impairs normal hematopoiesis, we analyzed total bone marrow cellularity and lineage frequency in Prmt7 KO (Vav1-Cre+) versus Prmt7-WT (Vav1-Cre-) mice via Cytek full-spectrum flow cytometry. While total BM cellularity was comparable, PRMT7 KO slightly increased the number of CD4⁺ or CD8⁺ T cells. These results suggest that although PRMT7 function is likely dispensable for normal hematopoiesis, PRMT7 loss may have a modest effect on T cell proliferation or activation. In future studies, we will confirm whether PRMT7 inhibition promotes anti-tumor T cell activity in-vivo, and whether the underlying mechanism is via MHC-I regulation. Overall, we have shown that PRMT7 depletion or pharmacological inhibition enhances T cell function in part by upregulating MHC-I. These findings suggest that combining PRMT7 inhibitors with immunotherapy could be a promising strategy to overcome AML's immune-cold properties.